Acute and chronic pain continue to be the most common complaints which physicians are asked to treat. While acute pain can be managed in most cases, physicians are constantly searching for new methods with fewer side effects and less risk of addiction to treat it. Chronic pain is a different matter all-together. It is estimated that over 60 billion dollars are spent annually on this disorder not including loss of productivity. At present, our understanding and ability to treat chronic pain are limited. the present proposal will investigate the brain's own capacity to modulate pain. A thorough understanding of these mechanisms is essential for the rational development of new therapies for the treatment of acute and chronic pain. The continuing long term objective of this proposal is to determine the cellular and synaptic mechanisms by which sensory input to the dorsal horn and in particular the marginal zone (lamina I) and substantia gelatinosa (lamina II) is modulated by higher brain centers. The specific aims of this five year proposal are to: 1) continue to define the functional effects of focal brain stem stimulation on physiologically and anatomically identified marginal zone and substantia gelatinosa interneurons as well as marginal zone neurons identified as projecting to the midbrain; 2) determine the putative neurotransmitter utilized by identified descending fibers by using immuno-cytochemical double labeling techniques both at the light and electron microscopic level; 3) determine the physiological chacteristics of inhibitory interneurons in the marginal zone and substantia gelatinosa by using intracellular recording and labeling combined with immunocytochemical labeling both at the light and electron microscopic level;l 4) determine the effects of stimulating descending systems on the expression of the proto-oncogene, c-fos, in spinal cord neurons; 5) determine the characteristics of neurons in the parabrachial region of the midbrain/pontine junction which receive nociceptive inputs from the spinal cord. These specific aims will be accomplished by using techniques which combine intracellular recording of neurons with intracellular labeling so that the neuron and its axonal arbor can be examined with the light and electron microscopes. Putative neurotransmitters in these neurons will be assessed by using immunocytochemical techniques at both light and electron microscopic levels. Immunocytochemical techniques will also be used to demonstrate the expression of c-fos which will be used as a marker of cellular modulation by descending pathways.